论文一
论文标题：SARS-CoV-2 infection triggers paracrine senescence and leads to a sustained senescence-associated inflammatory response
作者：Tsuji, Shunya, Minami, Shohei, Hashimoto, Rina, Konishi, Yusuke, Suzuki, Tatsuya, Kondo, Tamae, Sasai, Miwa, Torii, Shiho, Ono, Chikako, Shichinohe, Shintaro, Sato, Shintaro, Wakita, Masahiro, Okumura, Shintaro, Nakano, Sosuke, Matsudaira, Tatsuyuki, Matsumoto, Tomonori, Kawamoto, Shimpei, Yamamoto, Masahiro, Watanabe, Tokiko, Matsuura, Yoshiharu, Takayama, Kazuo, Kobayashi, Takeshi, Okamoto, Toru, Hara, Eiji
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期刊：Nature Aging
发表时间：2022/01/25
数字识别码：10.1038/s43587-022-00170-7
摘要：Reports of post-acute COVID-19 syndrome, in which the inflammatory response persists even after SARS-CoV-2 has disappeared, are increasing1, but the underlying mechanisms of post-acute COVID-19 syndrome remain unknown. Here, we show that SARS-CoV-2-infected cells trigger senescence-like cell-cycle arrest2,3 in neighboring uninfected cells in a paracrine manner via virus-induced cytokine production. In cultured human cells or bronchial organoids, these SASR-CoV-2 infection-induced senescent cells express high levels of a series of inflammatory factors known as senescence-associated secretory phenotypes (SASPs)4 in a sustained manner, even after SARS-CoV-2 is no longer detectable. We also show that the expression of the senescence marker CDKN2A (refs. 5,6) and various SASP factor4 genes is increased in the pulmonary cells of patients with severe post-acute COVID-19 syndrome. Furthermore, we find that mice exposed to a mouse-adapted strain of SARS-CoV-2 exhibit prolonged signs of cellular senescence and SASP in the lung at 14 days after infection when the virus was undetectable, which could be substantially reduced by the administration of senolytic drugs7. The sustained infection-induced paracrine senescence described here may be involved in the long-term inflammation caused by SARS-CoV-2 infection. https://www.nature.com/articles/s43587-022-00170-7
论文二
论文标题：Senolytics reduce coronavirus-related mortality in old mice
作者：Christina D. Camell , Matthew J. Yousefzadeh , Yi Zhu , Larissa G. P. Langhi Prata , Matthew A. Huggins , Mark Pierson , Lei Zhang , Ryan D. O’Kelly , Tamar Pirtskhalava , Pengcheng Xun , Keisuke Ejima , Ailing Xue , Utkarsh Tripathi , Jair Machado Espindola-Netto , Nino Giorgadze , Elizabeth J. Atkinson , Christina L. Inman , Kurt O. Johnson , Stephanie H. Cholensky , Timothy W. Carlson , Nathan K. LeBrasseur , Sundeep Khosla , M. Gerard O’Sullivan , David B. Allison , Stephen C. Jameson , Alexander Meves , Ming Li , Y. S. Prakash , Sergio E. Chiarella , Sara E. Hamilton , Tamara Tchkonia , Laura J. Niedernhofer , James L. Kirkland , Paul D. Robbins
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期刊：Science
发表时间：2021/07/16
数字识别码：10.1126/science.abe4832
摘要：The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically ill to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnCs) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 spike protein-1, increasing expression of viral entry proteins and reducing antiviral gene expression in non-SnCs through a paracrine mechanism. Old mice acutely infected with pathogens that included a SARS-CoV-2–related mouse β-coronavirus experienced increased senescence and inflammation, with nearly 100% mortality. Targeting SnCs by using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased antiviral antibodies. Thus, reducing the SnC burden in diseased or aged individuals should enhance resilience and reduce mortality after viral infection, including that of SARS-CoV-2. https://www.science.org/doi/10.1126/science.abe4832
论文三
论文标题：Virus-induced senescence is a driver and therapeutic target in COVID-19
作者：Lee, Soyoung, Yu, Yong, Trimpert, Jakob, Benthani, Fahad, Mairhofer, Mario, Richter-Pechanska, Paulina, Wyler, Emanuel, Belenki, Dimitri, Kaltenbrunner, Sabine, Pammer, Maria, Kausche, Lea, Firsching, Theresa C., Dietert, Kristina, Schotsaert, Michael, Martínez-Romero, Carles, Singh, Gagandeep, Kunz, Séverine, Niemeyer, Daniela, Ghanem, Riad, Salzer, Helmut J. F., Paar, Christian, Mülleder, Michael, Uccellini, Melissa, Michaelis, Edward G., Khan, Amjad, Lau, Andrea, Schönlein, Martin, Habringer, Anna, Tomasits, Josef, Adler, Julia M., Kimeswenger, Susanne, Gruber, Achim D., Hoetzenecker, Wolfram, Steinkellner, Herta, Purfürst, Bettina, Motz, Reinhard, Di Pierro, Francesco, Lamprecht, Bernd, Osterrieder, Nikolaus, Landthaler, Markus, Drosten, Christian, García-Sastre, Adolfo, Langer, Rupert, Ralser, Markus, Eils, Roland, Reimann, Maurice, Fan, Dorothy N. Y., Schmitt, Clemens A.
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期刊：Nature
发表时间：2021/09/13
数字识别码：10.1038/s41586-021-03995-1
摘要：Derailed cytokine and immune cell networks account for organ damage and clinical severity of COVID-191–4. Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and accompanied by a senescence-associated secretory phenotype (SASP), composed of pro-inflammatory cytokines, extracellular matrix-active factors and pro-coagulatory mediators5–7. COVID-19 patients displayed markers of senescence in their airway mucosa in situ and elevated serum levels of SASP factors. Mirroring COVID-19 hallmark features such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue1,8,9, in vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, neutrophil extracellular trap (NET) formation as well as activation of platelets and the clotting cascade in response to supernatant of VIS cells, including SARS-CoV-2-induced senescence. Senolytics such as Navitoclax and Dasatinib/Quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-driven hamster and mouse models. Our findings mark VIS as pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest senolytic targeting of virus-infected cells as a novel treatment option against SARS-CoV-2 and perhaps other viral infections. https://www.nature.com/articles/s41586-021-03995-1
在此之前，2021年7月16日，美国明尼苏达大学和梅奥医学中心的研究团队在 Science 期刊发表了题为：Senolytics reduce coronavirus-related mortality in old mice 的研究论文【2】。这项研究表明，抗衰老药物Senolytics能够降低老年小鼠与冠状病毒相关的死亡率。
2021年9月13日，德国柏林夏里特医学院的研究人员在 Nature 上发表了题为：Virus-induced senescence is driver and therapeutic target in COVID-19 的研究论文【3】。
